Coste Franck, Ober Matthias, Le Bihan Yann-Vaï, Izquierdo Maria Angeles, Hervouet Nadège, Mueller Heiko, Carell Thomas, Castaing Bertrand
Centre de Biophysique Moléculaire, UPR4301, CNRS, rue Charles Sadron, 45071 Orléans cedex 02, France.
Chem Biol. 2008 Jul 21;15(7):706-17. doi: 10.1016/j.chembiol.2008.05.014.
Fpg is a bacterial base excision repair enzyme that removes oxidized purines from DNA. This work shows that Fpg and its eukaryote homolog Ogg1 recognize with high affinity FapydG and bulky N7-benzyl-FapydG (Bz-FapydG). The comparative crystal structure analysis of stable complexes between Fpg and carbocyclic cFapydG or Bz-cFapydG nucleoside-containing DNA provides the molecular basis of the ability of Fpg to bind both lesions with the same affinity and to differently process them. To accommodate the steric hindrance of the benzyl group, Fpg selects the adequate rotamer of the extrahelical Bz-cFapydG formamido group, forcing the bulky group to go outside the binding pocket. Contrary to the binding mode of cFapydG, the particular recognition of Bz-cFapydG leads the BER enzymes to unproductive complexes which would hide the lesion and slow down its repair by the NER machinery.
Fpg是一种细菌碱基切除修复酶，可从DNA中去除氧化嘌呤。这项研究表明，Fpg及其真核生物同源物Ogg1对FapydG和大分子N7-苄基-FapydG（Bz-FapydG）具有高亲和力。Fpg与含碳环cFapydG或Bz-cFapydG核苷的DNA之间稳定复合物的比较晶体结构分析，为Fpg以相同亲和力结合两种损伤并对其进行不同处理的能力提供了分子基础。为了适应苄基的空间位阻，Fpg选择了螺旋外Bz-cFapydG甲酰胺基团的合适旋转异构体，迫使大分子基团离开结合口袋。与cFapydG的结合模式相反，Bz-cFapydG的特殊识别导致碱基切除修复酶形成非生产性复合物，这会掩盖损伤并减缓核酸切除修复机制对其的修复。
